One-third of inherited human diseases are caused by mutated mRNAs harboring premature termination codons (PTCs). Nonsense-mediated mRNA decay (NMD) is a critical cellular surveillance mechanism that recognizes and eliminates aberrant RNAs containing PTC. NMD plays an important role in cell cycle regulation, cell viability, and DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism can lead to pathologies, including neurological disorders, immune diseases and cancers. Data estimate that ~22% of disease-causing PTCs are predicted to be insensitive to NMD. Therefore, controlling NMD activity is an attractive approach to developing novel therapeutics for many human diseases.
Rochester researchers have developed a method to suppress NMD-insensitive transcripts using cutting-edge CRISPR-Cas13 technology, namely the RNAProgrammed NMD Activation (RP-NMDA) system. This system will be tested on the Human Beta-globin gene (HBB) and human colorectal cancer cell lines.
The proposed strategy utilizes the CRISPR-Cas13 system, which is more specific than the miRNA-based system without showing any off-target effects. Thus, this approach selectively targets NMD-insensitive PTCs that fail to trigger NMD, regardless of their reading frames.